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The long-term efficacy and tolerability of donepezil in patients with vascular dementia

The long-term efficacy and tolerability of donepezil inpatients with vascular dementia
David Wilkinson1, Gustavo Ro´man2, Stephen Salloway3, Jane Hecker4, Karyn Boundy5, Dinesh Kumar6,Holly Posner7 and Rachel Schindler7
1Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK
2University of Texas Medical School at San Antonio, San Antonio, TX, USA
3Memory and Aging Program, Butler Hospital, Providence, RI, USA
4Memory Disorders Study Unit, Repatriation General Hospital, Daw Park, Australia
5Department of Neurology, Queen Elizabeth Hospital, Woodville, Australia
6Eisai Inc., Woodcliff Lake, NJ, USA
7Pfizer Inc., New York, NY, USA
Correspondence to: D. Wilkinson, E-mail: David.Wilkinson@hantspt-sw.nhs.uk
Objective: To determine the long-term tolerability and efficacy of donepezil in patients with vasculardementia (VaD).
Methods: International, multicentre, open-label, 30-week extension study of two 24-week, randomised,double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age,74.7 0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease,who were medically stable and had completed one of two double-blind studies. All patients receiveddonepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments wereperformed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer'sdisease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverseevents (AEs) and physical and laboratory evaluations.
Results: Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study;127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6–1.15 points) from double-blindstudy baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patientswho received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group thatinitiated donepezil treatment during the extension study. Most common donepezil-related AEs werenausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred.
Conclusion: These data suggest that donepezil improves cognition for up to 54 weeks in patients withVaD. Patients initiating donepezil in this extension study did not perform as well on the primaryoutcome measure as those initiating donepezil in the double-blind study. Copyright # 2009 John Wiley& Sons, Ltd.
Key words: vascular dementia; donepezil; cholinesterase inhibitor; long-term trial; safety; tolerability; efficacyHistory: Received 20 January 2009; Accepted 21 May 2009; Published online 21 July 2009 in Wiley InterScience(www.interscience.wiley.com).DOI: 10.1002/gps.2340
throughout the world, there is currently no approvedtherapy for the symptomatic treatment of VaD (Doody
Vascular dementia (VaD), one of the most common
et al., 2001b), and treatment strategies generally focus
forms of dementia (Dubois and Hebert, 2001), results
on the control of underlying cardiovascular risk factors
from ischaemic injury to brain regions serving
such as the treatment of hypertension, correction of
memory, cognition and behaviour. In many countries
arrhythmias, smoking cessation, management of
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
D. Wilkinson et al.
hyperlipidaemia and control of metabolic disorders
evaluable patients entering the additional 36-week
such as diabetes.
extension phase ( 77 patients per original treatment
Given that brain lesions in patients with VaD may
group), as well as the potential for selection bias,
produce cholinergic dysfunction similar to that seen in
efficacy data beyond the original 30-week extension
patients with Alzheimer's disease (AD) (Tohgi et al.,
were not statistically viable and are not presented in the
1996), donepezil, a cholinesterase inhibitor (ChEI)
current report. Safety findings from the additional 36-
approved for the treatment of AD, was investigated for
week extension are reported.
the treatment of VaD. There have been two published24-week, double-blind, placebo-controlled trials ofdonepezil in patients with possible or probable VaD
Study entry criteria
(Black et al., 2003; Wilkinson et al., 2003), diagnosedclinically and radiologically using NINDS-AIREN
All patients who completed the double-blind studies
criteria (Roman et al., 2005). A combined analysis
were eligible for entry into the open-label study. Entry
of these studies (N ¼ 1219) showed that donepezil
criteria for the double-blind studies have been des-
provided significant improvements at study end
cribed previously (Black et al., 2003; Wilkinson et al.,
compared with placebo for cognition at both 5 and
2003; Roman et al., 2005). Briefly, men and women
10 mg/day doses, and for global function at the 5 mg/
aged at least 40 years with a diagnosis of probable or
day dose; donepezil was also well tolerated (Roman
possible VaD of at least 3 months' duration, Mini-
et al., 2005). A third, currently unpublished, trial of
Mental State Examination (MMSE) scores between 10
donepezil for VaD has been conducted, which was very
and 26, and with clinical and radiological evidence of
similar in scope and structure to the two published
cerebrovascular disease were included. Patients with
trials, except that screening computed tomography or
hypertension, diabetes, cardiac disease or stroke were
magnetic resonance imaging scans were reviewed
included provided these conditions had been stable for
centrally (Roman et al., 2006). As a result of available
at least 3 months. Patients with AD or other
trial data, donepezil is now licensed for the treatment
neurodegenerative disorders were excluded, as were
of VaD in Romania, India, South Korea, Thailand,
those with major psychiatric disorders or a history of
Vietnam, New Zealand and the Philippines.
drug or alcohol abuse. Most concomitant medications
The objective of the current study, an open-label
were permitted during the study, with the exception of
extension of the original double-blind studies (Black
other ChEIs and anticholinergics.
et al., 2003; Wilkinson et al., 2003), was to determine
All patients (or their legal representative) and their
the long-term safety and sustainability of efficacy in
caregivers provided voluntary, written informed con-
donepezil-treated patients, and to compare the effect of
sent for participation in the study. This study was
a delayed start to therapy in the placebo patients with
conducted in accordance with the ethical principles of
effects in patients continually treated with donepezil.
the Declaration of Helsinki, as amended, and inaccordance with local laws and regulations, whicheverafforded the greater protection for the participant.
In this open-label extension, all patients received
This was an open-label, 30-week extension study of two
donepezil 5 mg/day for the first 6 weeks and 10 mg/day
24-week, randomised, double-blind, placebo-con-
thereafter, if approved by a clinician (irrespective of
trolled, parallel-group studies in patients with possible
their assigned group during the double-blind studies),
or probable VaD. The study designs and results for the
for a total of 30 weeks. Patients were assessed at week 6
original trials have been published previously (Black
and thereafter at 12-week intervals. In the subset of
et al., 2003; Wilkinson et al., 2003). Study sites—
patients participating in the additional study exten-
conducted at 100 sites in the US, UK and Europe. For a
sion, donepezil was continued at the same dosage and
subset of sites in the United Kingdom, Ireland,
assessments were performed at weeks 42, 54 and 66.
Germany and Australia, the study was extended for
Vital signs and adverse events (AEs) were monitored at
an additional 36 weeks (total extension of 66 weeks);
each assessment. A physical and neurological examina-
this was for investigators who specifically made the
tion was also conducted and laboratory tests (clinical
request for their patient(s). Due to a small number of
chemistry, haematology and urinalysis) performed.
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia
study withdrawal were cerebrovascular accident (4[1.3%] placebo and 10 [1.7%] donepezil patients),
The primary efficacy measure was the Alzheimer's
asthenia (four [1.3%] placebo and six [1.0%] donepezil
disease Assessment Scale- cognitive subscale (ADAS-
patients) and nausea (five [1.7%] placebo and four
cog), a measure of cognitive function. Secondary
[0.7%] donepezil patients). All other AEs that led to
efficacy outcome measures were the Clinical Dementia
study discontinuation occurred in less than 1% of
Rating-Sum of the Boxes (CDR-SB), a measure of
overall disease severity; the MMSE, a second measureof cognitive function; and the Alzheimer's DiseaseFunctional Assessment and Change Scale (ADFACS), a
Patient characteristics
functional test assessing the patient's ability to performinstrumental activities of daily living (ADLs) and basic
No significant differences were found in the baseline
ADLs. Safety results were reported for all patients who
characteristics of the patients enrolled in this open-
received open-label treatment.
label study (sex, race, mean age, dementia severity)when compared with those of the initial double-blindstudies total cohort. Moreover, demographic charac-
Statistical analysis
teristics were similar regardless of original treatmentgroup (Table 1). Baseline characteristics of the patients
Efficacy analyses were performed on observed cases up
enrolled in the double-blind trials have been described
to week 30 of the open-label treatment (54 weeks since
previously (Roman et al., 2005).
the start of the double-blind studies) and summarised
During the 30-week open-label phase, 111 patients
using descriptive statistics. Results of outcome
(12.5%) remained on the 5 mg/day dose, 78 patients
measures were presented as mean change from the
(8.8%) had their dose increased to 10 mg/day but then
baseline score. Statistical analyses were conducted
returned to 5 mg/day and 696 (78.6%) patients
using analysis of covariance for the ADAS-cog. All
escalated to 10 mg/day donepezil and remained at this
patients randomised into the open-label extension
phase of the study were included in the safety analysis.
Nearly all patients (99.9%) took at least one
concomitant medication during the study. Theseincluded antithrombotic agents (85.4% of the total
population); vitamins (42.8%); agents acting on therenin–angiotensin system (36.6%); psychoanaleptics,
Patient disposition
including hypnotics, antidepressants and tranquillisers(38.2%) and serum lipid-reducing agents (31.4%).
Of the 1219 patients enrolled in the two double-blindstudies, 885 (72.6%) continued into the open-labelphase. In total, 707 (79.9%) of these 885 patients
completed the 30-week open-label extension. A subsetof 227 (32.1%) patients continued into the additional
Cognitive function. Results for the primary outcome
extension phase, of whom, 194 (85.5%) completed the
measure, the ADAS-cog, showed a mean change from
additional 36 weeks (Figure 1).
double-blind study baseline score to week 54 (24 weeks
A higher proportion of patients randomised to the
double-blind plus 30 weeks open-label) of between
placebo group during the original double-blind phase
0.6 and 1.15 points for patients who had received
discontinued during the 30-week open-label phase
donepezil at either dose for the entire 54 weeks
(23.6%) compared with the two donepezil groups
(Figure 2A). The mean ADAS-cog score for all the
(19.8 and 16.7% of patients from the original 5 and
donepezil-treated patients who elected to go into the
10 mg/day donepezil groups, respectively). During the
open-label study improved over baseline during
30-week open-label phase, a total of 108 (12.2%)
the double-blind trials and remained above baseline
subjects discontinued prematurely due to AEs: 43
for the entire open-label phase of the study. This
(39.8%) originally randomised to placebo, 36 (33.3%)
improvement was observed regardless of the initial
to 5 mg/day donepezil and 29 (26.9%) to 10 mg/day
randomised dosage (5 or 10 mg of donepezil) during
donepezil. During the additional 36-week extension,
the double-blind phase (Figure 2A).
19 (8.4%) of the subset of 227 patients withdrew due to
The initiation of donepezil treatment in patients
AEs. The most common individual AEs resulting in
who had been randomised to receive placebo in the
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.

D. Wilkinson et al.
Figure 1 Patient disposition.
double-blind trials and who elected to enter the open-
relative to placebo at the end of the double-blind
label phase produced no significant improvement in
studies and remained improved relative to baseline
their ADAS-cog scores, but their scores did remain
during the open-label study (Figure 2B). Patients in the
stable, close to their baseline values throughout the
delayed start group showed an ameliorated response
additional 30 weeks of treatment (Figure 2A).
with a smaller initial improvement, which was
The MMSE score in both the 5 and 10 mg/day
maintained above baseline for a shorter time
donepezil treatment groups was significantly improved
(Figure 2B).
Table 1 Patient demographics of the open-label phase
Treatment in double-blind phase
Donepezil 5 mg/day n ¼ 303
Donepezil 10 mg/day n ¼ 281
Male patients (%)
Mean ADAS-cog score (SE)
Mean MMSE score (SE)
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia
Figure 2 (A) Mean change from baseline ADAS-cog scores during double-blind and open-label treatment. (B) Mean change from baseline MMSE scoresduring double-blind and open-label treatment. (C) Mean change from baseline CDR-SB scores during double-blind and open-label treatment. (D) Meanchange from baseline ADFACS scores during double-blind and open-label treatment.Dosages in figure keys correspond to dosing schedule during double-blind phase only. During the open label extension, all patients received donepezil5 mg/day for the first 6 weeks and thereafter 10 mg/day, if approved by a clinician (76.6% of patients remained at 10 mg/day through study completion).ol ¼ open label.
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
D. Wilkinson et al.
Figure 2 (Continued).
Global function. Scores on the CDR-SB, which
label; Figure 2C). As with the ADAS-cog, patients
improved from baseline during the double-blind phase
randomised to the delayed start group did not
for both the 5 and 10 mg/day donepezil groups,
experience an improvement in their CDR-SB scores
remained improved relative to the double-blind study
following the initiation of donepezil treatment in the
baseline for 42 weeks of treatment (18 weeks open-
open-label phase; however, CDR-SB scores were stable
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia
during the 30 weeks of open-label treatment. At the
placebo patients (28.9% vs. 25.6%, respectively). Of the
end of the extension phase, there were no notable
cardiovascular events recorded during this study,
differences between the treatment groups.
hypertension (6.3% of all patients) and stroke
Although there was no significant difference
(4.7%) were the most common. There were 29 deaths
between the groups on the ADFACS scale at endpoint,
during the study or within 4 weeks of treatment
there was a trend suggesting that patients who had been
discontinuation: 7 (2.3%) among patients originally
randomised to 10 mg/day donepezil during the
randomised to placebo and 22 (3.8%) among patients
double-blind part of the study declined less during
originally randomised to donepezil in the double-blind
the open-label phase compared with either those
studies. The most common causes of death were
receiving donepezil 5 mg/day or the delayed start group
cerebrovascular accident, myocardial infarction and
(Figure 2D).
malignancy. There were four deaths that investigatorsattributed possibly to study medication: of these, twopatients died of a cardiovascular accident, one from
sepsis and one from multisystem failure.
Serious AEs were reported for 228 patients. The
Donepezil was well tolerated. Most AEs were mild to
most common were cerebrovascular accident (4.7%)
moderate in intensity. No new or unexpected AEs
and accidental injury (2.1%). There were no clinically
attributable to donepezil emerged during long-term
meaningful changes in clinical laboratory values, vital
treatment. The AEs that occurred during open-label
signs, physical examination findings or electrocardio-
treatment were the same as those observed during the
gram status during the study.
double-blind studies and they occurred with approxi-mately the same frequency in both phases, with 87.6%of patients in the open-label study and 90.2% of
patients in the double-blind studies reporting one ormore AE. The only AEs that occurred in more than
Improvements in cognitive function in patients with
10% of patients were diarrhoea (12.8%), accidental
VaD gained during the 24-week double-blind treat-
injury (12.5%) and infection (11.3%) (Table 2). AEs
ment with donepezil were maintained above baseline
judged to be related to donepezil treatment resulted
during a further 30 weeks of open-label treatment.
from expected cholinergic effects, most commonly
Patients receiving donepezil (either dose) for 54 weeks
nausea (occurring in 5.3% of all patients) and
had an improvement in their ADAS-cog score of up to
diarrhoea (occurring in 8.8% of all patients). All other
approximately one point from their baseline score,
drug-related treatment-emergent signs and symptoms
suggesting that continuous treatment with donepezil
occurred in less than 5% of the study population.
improves and sustains cognitive benefit for at least a
Treatment-emergent AEs related to the cardiovas-
year. Interestingly, although patients receiving 10 mg/
cular system occurred at a similar rate in treated and
day donepezil initially did better than those patients
Table 2 Incidence of most commonly occurring TESS (occurring in 5% of patients) during the open-label phase
No. (%) of patients experiencing TESS
Treatment in double-blind phasea
Donepezil 5 or 10 mg/day n ¼ 584
Accidental injury
Cardiovascular system
TESS ¼ treatment emergent signs and symptoms.aDosing during double-blind phase only. During the open label extension, all patients received donepezil 5 mg/day for the first 6 weeks and thereafter10 mg/day, if approved by a clinician (76.6% of patients remained at 10 mg/day through study completion).
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
D. Wilkinson et al.
receiving 5 mg/day on this test, after week 34 (i.e.
affected not only by cognition, but also by physical
10 weeks into the open-label phase) patients receiving
impairments/limitations the patient might have due to
5 mg/day donepezil had nonsignificantly better scores
stroke, congestive heart failure or to having experi-
on the ADAS-cog that were maintained relative to
enced a heart attack. Nonetheless, once started on
those of patients receiving 10 mg/day until the end of
therapy, functional ADLs appeared to stabilise in
the study. This pattern has been seen in a previous AD
open-label, extension study, where the ‘crossover'
The original two double-blind studies only enrolled
occurred after about 110 weeks of uninterrupted
patients with stable comorbid conditions, often several
donepezil therapy (Doody et al., 2001a). The small
months (at least 3) after a cardiovascular event.
number of patients in the 5 mg/day group might
Patients with VaD generally stabilise until the next
provide some explanation; however, the reason for this
event, which possibly explains why the original studies
result in the ADAS-cog remains unclear. Both doses of
showed that efficacy measure scores remained close to
donepezil (5 and 10 mg/day) were beneficial, and in the
baseline among placebo patients (Pratt, 2002), a
CDR-SB and the ADFACS tests in this study, the
plateau effect also seen in other VaD clinical trial
10 mg/day donepezil dose tended to be the more
populations (Kittner et al., 2000). Over time, however,
beneficial dose, suggesting that the discrepant results
as individual patients experience additional vascular
for the ADAS-cog may be attributable to the variability
events, accompanied by clinical deterioration—either
of the test.
stepwise or, more commonly, gradually—this would
By week 42, the mean MMSE score for all patients
begin to appear as a progressive group decline. Thus, a
was one point higher than at baseline. This is in
positive outcome for this study would include not only
contrast to the decline expected over this period with
a positive result for the treatment group on one or
no treatment. As change in the MMSE score can be
several of the assessment measures, but also stability or
directly correlated with clinical measures of function,
less than expected decline.
such as dressing and toileting activities (Galasko et al.,
Donepezil was generally well tolerated in this study,
1995), this sustained improvement in the MMSE may
in spite of patients having multiple comorbidities and
represent retention of function, which is important for
concomitant drug use. Moreover, tolerability data
both patient quality of life (Andersen et al., 2004;
from the 24-week trials were similar to the year-long
Wlodarczyk et al., 2004) and for caregivers. Unlike the
data, and the extension phase to 90 weeks, albeit with
ADAS-cog results, MMSE scores attained by patients in
fewer patients. This mirrors what has been observed in
the delayed-start group at 42 and 54 weeks were
clinical studies of AD patients, a population in which
comparable with those of patients who had received
safety data are available for up to 4.9 years (Doody
donepezil from study start. The ADAS-cog results,
et al., 2001b). It is, therefore, not unreasonable to
however, indicated that there was still a difference in
assume that donepezil can be tolerated over the long
the level of cognitive function between those patients
term in patients with VaD.
taking donepezil from study start and those with a
There are limitations to the present study. The open-
delay to initiation of active treatment. This may
label design of this extension phase does not allow
indicate that the ADAS-cog, which was designed
comparison of treated with untreated patients in the
specifically to test cognitive deficits associated with AD,
longer term. Although not ideal, open-label extension
is a less sensitive instrument in patients with VaD than
studies do provide important information and are
the MMSE, which is a general test of cognition.
necessary due to the ethical implications of performing
Results with the CDR-SB were similar to those seen
long-term, placebo-controlled studies in patients with
with ADAS-cog: that is, improvements gained by the 5
dementia. Another possible limitation of the study is
and 10 mg/day donepezil groups during double-blind
related to the donepezil dosing schedules. During the
treatment were mostly maintained above baseline
double-blind phase, donepezil-treated patients were
during the open-label phase, but patients who had been
randomised to receive either the 5 or 10 mg/day dose.
delayed in receiving donepezil generally did not
On enrolment in the open-label phase, all patients
improve upon initiation of donepezil treatment. The
received the 5 mg/day dose for 6 weeks, with some
effects of treatment on function (ADFACS) were
subsequently remaining on this dose, some increasing
mixed. Over the course of the study, the patients'
to the 10 mg/day dose temporarily, and most increas-
ability to carry out ADLs, as measured by this test,
ing to the 10 mg/day dose permanently. Although, it is
generally deteriorated, despite continued donepezil
important to consider the possible implications of
treatment. The evaluation of the ability to perform
these different dosage regimens when interpreting the
ADLs in patients with VaD is complicated and can be
current results, outcomes from the double-blind phase
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia
Donepezil was well tolerated over 6 months in
This study was sponsored by Eisai Inc. and Pfizer Inc.
patients with VaD; 14.4% discontinued due to
Study design, data collection and interpretation of the
AEs, with diarrhoea being the most common
results were conceived by the authors. Editorial
(incidence of 8.8%).
assistance was provided by R. Daniel, PhD, at PPSI
Patients treated with donepezil for 54 continuous
and was funded by Eisai Inc. and Pfizer Inc.
weeks (double-blind study plus extension study)had ADAS-cog scores at endpoint that werehigher than at baseline, including those who wererandomised to donepezil 5 mg/day in the double-
blind trial.
Patients who initiated donepezil during the open-
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Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.

Asian J Androl 2006; 8 (2): 219–224 .Clinical Experience .Long-term treatment with intracavernosal injections in diabetic men with erectile dysfunction P. Perimenis, A. Konstantinopoulos, P. P. Perimeni, K. Gyftopoulos, G. Kartsanis, E. Liatsikos, A. Athanasopoulos Department of Urology, University Hospital, 26500 Patras, Greece Aim: To assess the behavior of patients with diabetes mellitus (DM) and erectile dysfunction (ED) during 10 con-secutive years of treatment with self-injection of vasoactive drugs. Methods: Thirty-eight diabetic men, including 12with type I and 26 with type II diabetes, were followed up regularly for 10 years after they began self-injecting forsevere ED. Real time rigidity assessment was used for the objective determination of the initial dosage and then doseswere regulated in order to introduce an erection suitable for penetration and maintenance of erection for approximately30 min. Patients were followed up every two months, and doses were increased only when the treatment responsewas not satisfactory. Results: The number of injections used per year by the patients was reduced each year (meannumbers: 50 in the first year and 22.5 in the 10th) and treatment shifted towards stronger therapeutic modalities(mixtures of vasoactive drugs instead of prostaglandin E1 alone). Type I diabetic men were standardized to a level oftreatment as early as 5 years after the initiation of treatment. That level was finally reached by type II patients afteranother 4-5 years. Conclusion: Treatment with self-injections of vasoactive drugs in diabetic men with severe ED isa safe and effective alternative in the long term. Diabetic men of both types show the same preferences in quality andquantity of treatment after 10 years. The key point for maintenance in treatment is the adjustment of the therapeuticmethod and dosage to optimal levels for satisfactory erections. (Asian J Androl 2006 Mar; 8: 219–224)